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WO1996023485A1 - Particules porteuses a utiliser dans des inhalateurs a poudre seche - Google Patents

Particules porteuses a utiliser dans des inhalateurs a poudre seche Download PDF

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Publication number
WO1996023485A1
WO1996023485A1 PCT/GB1996/000215 GB9600215W WO9623485A1 WO 1996023485 A1 WO1996023485 A1 WO 1996023485A1 GB 9600215 W GB9600215 W GB 9600215W WO 9623485 A1 WO9623485 A1 WO 9623485A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
powder
carrier particles
additive material
active
Prior art date
Application number
PCT/GB1996/000215
Other languages
English (en)
Inventor
John Nicholas Staniforth
Original Assignee
Co-Ordinated Drug Development Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10768844&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1996023485(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EP96901439A priority Critical patent/EP0806938B1/fr
Priority to CA002211874A priority patent/CA2211874C/fr
Priority to EA199700153A priority patent/EA000352B1/ru
Priority to AT96901439T priority patent/ATE256450T1/de
Priority to NZ300654A priority patent/NZ300654A/
Priority to SK1036-97A priority patent/SK282630B6/sk
Priority to BRPI9612950A priority patent/BRPI9612950B8/pt
Priority to DK02007397T priority patent/DK1232745T3/da
Priority to BRPI9607490 priority patent/BR9607490A/pt
Priority to AU45456/96A priority patent/AU699131B2/en
Priority to GEAP19963854A priority patent/GEP19991687B/en
Priority to DE69631119T priority patent/DE69631119T2/de
Priority to UA97084422A priority patent/UA61051C2/uk
Application filed by Co-Ordinated Drug Development Limited filed Critical Co-Ordinated Drug Development Limited
Priority to HU9802209A priority patent/HU229965B1/hu
Priority to DK96901439T priority patent/DK0806938T3/da
Priority to CNB961926767A priority patent/CN1303974C/zh
Priority to PL96321572A priority patent/PL186757B1/pl
Priority to US08/875,391 priority patent/US6153224A/en
Priority to JP52335096A priority patent/JP4042867B2/ja
Priority to EE9700176A priority patent/EE9700176A/
Publication of WO1996023485A1 publication Critical patent/WO1996023485A1/fr
Priority to IS4531A priority patent/IS4531A/is
Priority to NO19973502A priority patent/NO324037B1/no
Priority to FI973151A priority patent/FI119676B/fi
Priority to BG101858A priority patent/BG101858A/
Priority to US10/306,865 priority patent/US7011818B2/en
Priority to US11/202,741 priority patent/US7718163B2/en
Priority to US12/748,275 priority patent/US8920781B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • This invention relates to carrier particles for use in dry powder inhalers. More particularly the invention relates to a method of producing such particles, to a dry powder incorporating the particles and to the particles themselves.
  • Inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation. Inhalers are widely used particularly in the treatment of diseases of the respiratory tract.
  • inhaler There are a number of types of inhaler currently available. The most widely used type is a pressurised metered dose inhaler (MDI) which uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract. Those devices are disadvantageous on environmental grounds as they often use CFC propellants, and on clinical grounds related to the inhalation characteristics of the devices.
  • MDI pressurised metered dose inhaler
  • An alternative device to the MDI is the dry powder inhaler.
  • the delivery of dry powder particles of pharmaceutical products to the respiratory tract presents certain problems.
  • the inhaler should deliver the maximum possible proportion of the active particles expelled to the lungs, including a significant proportion to the lower lung, preferably at the low inhalation capabilities to which some patients, especially asthmatics, are limited. It has been found, however, that, when currently available dry powder inhaler devices are used, in many cases only about 10% of the active particles that leave the device on inhalation are deposited in the lower lung. More efficient dry powder inhalers would give clinical benefits
  • the type of dry powder inhaler used is of sig ⁇ nificant importance to the efficiency of delivery over a range of airflow conditions of the active particles to the respiratory tract. Also, the physical properties of the active particles used affect both the efficiency and reproducibility of delivery of the active particles and the site of deposition in the respiratory tract.
  • the active par- tides should form a physically and chemically stable aerocolloid which remains in suspension until it reaches a conducting bronchiole or smaller branching of the pulmonary tree or other absorption site preferably in the lower lung.
  • the active particle should be capable of efficient collection by the pulmonary mucosa with no active particles being exhaled from the absorption site.
  • the size of the active particles is important.
  • the active particles should be small, with an equivalent aerodynamic diameter substantially in the range of 0.1 to 5 ⁇ m, approximately spherical and monodispersed in the respiratory tract.
  • Small particles are, however, thermodyna ically unstable due to their high surface area to volume ratio, which provides significant excess surface free energy and encourages particles to agglomerate.
  • agglomeration of small particles and adherence of particles to the walls of the inhaler are problems that result in the active particles leaving the inhaler as large agglomerates or being unable to leave the inhaler and remaining adhered to the interior of the inhaler.
  • one type of dry powder for use in dry powder inhalers may include carrier particles to which the fine active particles adhere whilst in the inhaler device, but which are dispersed from the surfaces of the carrier particles on inhalation into the respiratory tract to give a fine suspension.
  • the carrier particles are often large particles greater than 90 ⁇ m in diameter to give good flow properties as indicated above. Small particles with a diameter of less than lO ⁇ m may be deposited on the wall of the delivery device and have poor flow and entrainment properties leading to poor dose uniformity.
  • the increased efficiency of redispersion of the fine active particles from the agglomerates or from the surfaces of carrier particles during inhalation is regarded as a critical step in improving the efficiency of the dry powder inhalers.
  • the shape and texture of the carrier particle should be such as to give sufficient adhesion force to hold the active particles to the surface of the carrier particle during fabrication of the dry powder and in the delivery device before use, but that force of adhesion should be low enough to allow the dispersion of the active particles in the respiratory tract.
  • the presence of additive particles which are attached to the surfaces of the carrier particles to promote the release of the active particles from the carrier particles is advantageous provided that the additive particles are not added in such a quantity that the active particles segregate from the surfaces of the carrier particles during fabrication of the dry powder and in the delivery device before use. Furthermore, we have found that the required amount of the additive particles is surprisingly small and that, if a greater amount is added, there will be no additional benefit in terms of inhalation performance but it will adversely affect the ability to process the mix.
  • the required amount of additive particles varies according to the composition of the particles - in the case where the additive particles are of magnesium stearate (that being a material that may be used but is not preferred) , we have found that an amount of 1.5 per cent by weight based on the total weight of the powder is too great and causes premature segregation of the active particles from the carrier particles. We believe that the same considerations apply in the case of Aerosil 200.
  • the present invention provides a powder for use in a dry powder inhaler, the powder including active particles and carrier particles for carrying the active particles, the powder further including additive material on the surfaces of the carrier particles to promote the release of the active particles from the carrier particles on actuation of the inhaler, the powder being such that the active particles are not liable to be released from the carrier particles before actuation of the inhaler.
  • Actuation of the inhaler refers to the process during which a dose of the powder is removed from its rest position in the inhaler, usually by a patient inhaling. That step takes place after the powder has been loaded into the inhaler ready for use.
  • the surface of a carrier particle is not usually smooth but has asperities and clefts in its surface.
  • the site of an asperity or of a cleft is believed to be an area of high surface energy.
  • the active particles are preferentially attracted to and adhere most strongly to those high energy sites causing uneven and reduced deposition of the active particles on the carrier surface. If an active particle adheres to a high energy site, it is subjected to a greater adhesion force than a particle at a lower energy site on the carrier particle and will therefore be less likely to be able to leave the surface of the carrier particle on actuation of the inhaler and be dispersed in the respiratory tract. It would therefore be highly advantageous to decrease the number of those high energy sites available to the active particles.
  • Additive material is attracted to and adheres to the high energy sites on the surfaces of the carrier par- tides. On introduction of the active particles, many of the high energy sites are now occupied, and the active particles therefore occupy the lower energy sites on the surfaces of the carrier particles. That results in the easier and more efficient release of the active particles in the airstream created on inhalation, thereby giving increased deposition of the active particles in the lungs.
  • the additive material will most advantageously be one that is safe to inhale into the lungs, it is still preferred that only a very small proportion, if any, of the additive material reaches the lung, in particular the lower lung.
  • the considerations that apply when selecting the additive material and other features of the powder are therefore different from the considerations when a third component is added to carrier and active material for certain other reasons, for example to improve absorption of the active material in the lung, in which case it would of course be advantage- ous for as much as possible of the additive material in the powder to reach the lung.
  • the amount of additive material in the powder should be not more than 10%, more advantageously not more than 5%, preferably not more than 4% and for most materials will be not more than 2% or less by weight based on the weight of the powder. In certain Examples described below the amount is about 1%.
  • the additive material is an anti- adherent material and will tend to decrease the cohesion between the active particles and the carrier particles.
  • the additive material is an anti ⁇ friction agent (glidant) and will give better flow of powder in the dry powder inhaler which will lead to better dose reproducibility from the inhaler.
  • an anti-adherent material or to an anti-friction agent
  • the reference is to include those materials which will tend to decrease the cohesion between the active particles and the carrier particles, or which will tend to improve the flow of powder in the inhaler, even though they may not usually be referred to as an anti-adherent material or an anti ⁇ friction agent.
  • leucine is an anti-adherent material as herein defined and is generally thought of as an anti-adherent material but lecithin is also an anti- adherent material as herein defined, even though it is not generally thought of as being anti-adherent, because it will tend to decrease the cohesion between the active particles and the carrier particles.
  • the carrier particles may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation.
  • the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols.
  • the carrier particles are particles of lactose.
  • substantially all (by weight) of the carrier particles have a diameter which lies between 20 ⁇ m and lOOO ⁇ m, more preferably 50 ⁇ m and lOOO ⁇ m.
  • the diameter of substantially all (by weight) of the carrier particles is less than 355 ⁇ m and lies between 20 ⁇ m and 250 ⁇ m.
  • at least 90% by weight of the carrier particles have a diameter between from 60 ⁇ m to 180 ⁇ m.
  • the relatively large diameter of the carrier particles improves the opportunity for other, smaller particles to become attached to the surfaces of the carrier particles and to provide good flow and entrainment characteristics and improved release of the active particles in the airways to increase deposition of the active particles in the lower lung.
  • the diameter of the particles referred to is the aerodynamic diameter of the particles.
  • the additive material consists of physiologically acceptable material.
  • the additive material may include a combination of one or more materials. It will be appreciated that the chemical composition of the additive material is of particular importance.
  • the additive material is a naturally occurring animal or plant substance.
  • the additive material includes one or more compounds selected from amino acids and derivatives thereof, and peptides and polypeptides having molecular weight from 0.25 to 1000 KDa, and derivatives thereof.
  • Amino acids, peptides or polypeptides and their deriva ⁇ tives are both physiologically acceptable and give acceptable release of the active particles on inhalation.
  • the additive material may comprise an amino acid.
  • Amino acids have been found to give, when present in low amounts in the powders as additive material, high respirable fraction of the active materials with little segregation of the powder and also with very little of the amino acid being transported into the lower lung.
  • leucine a preferred amino acid, it is found that, for example, for an average dose of powder only about lO ⁇ g of leucine would reach the lower lung.
  • the additive material may comprise one or more of any of the following amino acids: leucine, isoleucine, lysine, valine, methionine, phenyla- lanine.
  • the additive may be a salt or a derivative of an amino acid, for example aspartame or acesulfame K.
  • the additive particles consist substantially of leucine, advantageously L-leucine.
  • leucine has been found to give particularly efficient release of the active particles on inhalation.
  • the L-form of the amino acids is used in Examples described below, the D- and DL-forms may also be used.
  • the additive material may include one or more water soluble substances. This helps absorption of the substance by the body if the additive reaches the lower lung.
  • the additive material may include dipolar ions, which may consist of zwitterions.
  • the additive material may comprise particles of a phospholipid or a derivative thereof. Lecithin has been found to be a good material for the additive material.
  • the additive material may include or consist of one or more surface active materials, in particular materials that are surface active in the solid state, which may be water soluble, for example lecithin, in particular soya lecithin, or substantially water insoluble, for example solid state fatty acids such as lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof.
  • surface active materials in particular materials that are surface active in the solid state, which may be water soluble, for example lecithin, in particular soya lecithin, or substantially water insoluble, for example solid state fatty acids such as lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof.
  • Such materials are: magnesium stearate; sodium stearyl fumarate; sodium stearyl lactylate; phospatidylcholines, phosphatidylglycerols and other examples of natural and synthetic lung surfactants; Liposomal formulations; lauric acid and its salts, for example, sodium lauryl sulphate, magnesium lauryl sulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugar esters in general.
  • Other possible additive materials include talc, titanium dioxide, aluminium dioxide, silicon dioxide and starch.
  • magnesium stearate is highly surface active and should therefore be added in particularly small amounts; phosphatidylcholines and phosphatidylglycerols on the other hand are less active and can usefully be added in greater amounts; in respect of leucine, which is still less active, an addition of 2% by weight leucine based on the weight of the powder gives good results in respect of the respirable fraction of the active particles, low segregation and low amount of leucine reaching the lower lung; an addition of a greater amount does not improve the results and in particular does not significantly improve the respirable fraction and therefore whilst even with 6% leucine a reasonable result is obtained that is not preferred since it results in an increased quantity of additive material being taken into the body and will adversely affect the processing properties of the mix.
  • the additive material will often be added in particulate form but it may be added in liquid or solid form and for some materials, especially where it may not be easy to form particles of the material and/or where those particles should be especially small, it may be preferred to add the material in a liquid, for example as a suspension or a solution. Even then, however, the additive material of the finished powder may be in particulate form.
  • An alternative possibility, however, that is within the scope of the invention is to use an additive material which remains liquid even in the final essentially particulate material which can still be described as a "dry powder".
  • the additive material is not in the form of particles of material.
  • the additive material is less likely to leave the surface of the carrier particle and be transported into the lower lung.
  • the nature of the particles may be significant.
  • the additive particles may be non-spherical in shape. In Examples 1 to 3 below, the additive particles are plate-like particles. Alternatively the additive particles may be angular for example prisms, or dendritic in shape. Additive particles which are non- spherical may be easier to remove from the surfaces of the carrier particles than spherical, non-angular particles and plate-like particles may give improved surface interaction and glidant action between the carrier particles.
  • the surface area of the additive particles is also thought to be important.
  • the surface area of the additive particles as measured using gas absorption techniques, is preferably at least 5m 2 g _1 . In many cases it is found that additive material comprising small plate-like particles is preferred.
  • At least 95% by weight of the additive particles have a diameter less than 150 ⁇ m, more advantageously less than lOO ⁇ m, preferably less than 50 ⁇ m.
  • the mass median diameter of the additive particles is not more than about lO ⁇ m.
  • the additive particles preferably have a mass median diameter less than the mass median diameter of the carrier particles and will usually have a mass median diameter of approximately between a tenth and a hundredth that of the carrier particles.
  • the diameter of the particles may be calculated by laser diffraction or by another method by which the aerodynamic diameter of the particles can be determined.
  • the ratio in which the carrier particles, additive material and active particles are mixed will, of course, depend on the type of inhaler device used, the type of active particles used and the required dose. As indi ⁇ cated above, the amount of additive material is of particular importance. Advantageously the amount is in the range of from 0.1 to 10% by weight of the additive material based on the weight of the carrier particles.
  • the powder preferably consists of not less than 0.1% by weight of additive material based on the weight of the carrier particles and the powder preferably consists of at least 0.1% by weight of active particles based on the weight of the powder.
  • the carrier particles are preferably present in an amount of at least 90%, more preferably at least 95%, by weight based on the weight of the powder.
  • coating is an important and advantageous feature of the present invention.
  • the additive material whilst providing only a discontinuous covering for the carrier particles, does saturate the surfaces of the carrier particles in the sense that even if more additive material were provided substantially the same covering of the carrier particles would be achieved.
  • some of the additive particles may act as carriers of active particles and may be separate from or may separate from the surfaces of the carrier particles with active particles attached to their surfaces.
  • the dimensions of the combined active particle and additive particle may still be within the optimum values for good deposition in the lower lung. It is believed that active particles which adhere to the additive particles on the carrier particles may in some cases be preferentially released from the surfaces of the carrier particles and thereafter be deposited in the lower lung without the additive particles.
  • the mass median diameter of the active particles is not more than lO ⁇ m, preferably not more than 5 ⁇ m.
  • the particles therefore give a good suspension on redispersion from the carrier particles and are delivered deep into the respiratory tract.
  • the diameter of the particles may be calculated by laser diffraction or another method by which the aerodynamic diameter of the particles can be determined.
  • the active material referred to throughout the specification will be material of one or a mixture of pharmaceutical product(s) . It will be understood that the term “active material” includes material which is biologically active, in the sense that it is able to increase or decrease the rate of a process in a biological environment.
  • the pharmaceutical products include those products which are usually administered orally by inhalation for the treatment of disease such as respiratory disease eg. /.-agonists, salbutamol and its salts, salmeterol and its salts.
  • Other pharmaceutical products which could be administered using a dry powder inhaler include peptides and polypeptides, such as DNase, leucotrienes and insulin.
  • the active particles may include a 0 2 -agonist which may be terbutaline, a salt of terbutaline, for example terbutaline sulphate, or a combination thereof or may be salbutamol, a salt of salbutamol or a combination thereof.
  • Salbutamol and its salts are widely used in the treatment of respiratory disease.
  • the active particles may be particles of salbutamol sulphate.
  • the active particles may be particles of ipatropium bromide.
  • the active particles may include a steroid, which may be beclo ethasone dipropionate or may be Fluticasone.
  • the active principle may include a cromone which may be sodium cromoglycate or nedocro il.
  • the active principle may include a leukotriene receptor antagonist.
  • the active particles may include a carbohydrate, for example heparin.
  • particles for use in a powder as described above including carrier particles of a first composition and of a size suitable for use in a dry powder inhaler and additive material of a second composi ⁇ tion, the additive material being attached to the surfaces of the carrier particles.
  • the invention also provides a powder for use in a dry powder inhaler, the powder including active particles and carrier particles for carrying the active particles wherein the powder further includes additive material which is attached to the surfaces of the carrier particles to promote the release of the active particles from the carrier particles.
  • a method of producing particles suitable for use as particles in dry powder inhalers including the step of mixing carrier particles of a size suitable for use in dry powder inhalers with additive material which becomes attached to the surfaces of the carrier particles.
  • Additive material which may be in liquid form or may comprise additive particles, or agglomerates of additive particles, may be introduced to a sample of carrier particles, which may have been treated as described below, and the mixture blended to allow the additive material to become attached to the surfaces of the carrier particles.
  • the method advantageously further includes the step of selecting from a sample of carrier particles an advantageous range of size of carrier particles prior to the mixing step and, in the case where the additive material is in the form of particles when it is mixed with the carrier particles, preferably also includes the step of selecting from a sample of additive particles an advantageous range of size of additive particles prior to the mixing step.
  • the step of selecting an advantageous range of size may be a sieving step.
  • the additive material and the carrier particles are mixed for between 0.1 hours and 0.5 hours.
  • the particles may be mixed using a tumbling blender (for example a Turbula Mixer) .
  • the method further includes the step of treating the carrier particles to dislodge small grains from the surfaces of the carrier particles, without substantially changing the size of the carrier particles during the treatment.
  • the surface of a carrier particle is not usually smooth but has asperities and clefts in the surface. As a result, the surfaces have areas of high surface energy to which active particles are preferentially attached.
  • An active particle at a high energy site is less likely to be able to leave the surface and be dispersed in the respiratory tract than an active particle at a site of lower surface energy.
  • asperities are removed as small grains, thus removing active sites associated with the asperities.
  • the mixing step is prior to the treatment step.
  • the additive material may therefore be added in the form of large particles which are broken into smaller particles during the treatment.
  • the treatment may be carried out before the addition of the additive material or, alternatively, after the addition of the additive material and of the active particles.
  • the small grains become reattached to the surfaces of the carrier particles.
  • the object of treating the carrier particles is to reduce the number of high energy sites on the carrier particle surfaces, thus allowing an even deposition of active particles adhered on the surface with a force of adhesion such that dispersion of the active particles during inhalation is efficient.
  • the surfaces of the carrier particle have other high energy sites, for example at the site of clefts, which sites are not necessarily removed when the asperities are removed. It is highly advantageous to decrease the number of high energy sites.
  • the grains removed from the surface are small and thermodynamically unstable and are attracted to and adhere to the remaining high energy sites on the surface of the carrier particles.
  • the additive particles are attracted to the high energy sites which therefore can become saturated. That situation is highly preferable as is described above.
  • the active particles On introduction of the active particles, many of the high energy sites are already occupied, and the active particles therefore occupy the lower energy sites on the carrier particle surface, or on the surface of the additive particles. That results in the more efficient release of the active particles in the airstream created on inhalation, thereby giving increased deposition of the active particles in the lungs.
  • carrier particles refers to the particles on which the small grains become attached. References to carrier particles above, for example in respect of particle size, do not therefore include those small grains.
  • the treatment step is a milling step.
  • the milling causes asperities on the surfaces of the carrier particles to be dislodged as small grains. Many of those small grains become reattached to the surfaces of the carrier particles at areas of high energy as described above.
  • the milling step is performed in a ball mill.
  • the particles may be milled using plastics balls, or they may be milled using metal balls. Balls made of polypropylene material give less aggressive milling, whilst steel balls confer more aggressive action.
  • the mill may be rotated at a speed of about 60 revolutions per minute.
  • the mill may alternatively be rotated at a speed less than 60 revolutions per minute, for example at a speed of less than about 20 revolutions per minute, or for example a speed of about six revolutions per minute. That is a slow speed for ball milling and results in the gentle removal of grains from the surfaces of the particles and little fracture of the particles. Widespread fracture of the particles, which occurs with aggressive milling conditions, or at long milling times, may result in agglomerates of fractured particles of carrier material.
  • the particles are milled for at least 0.25 hours, preferably the particles are milled for not longer than about 6 hours. That time has been found to be suitable when milling with balls made from plastics material. When using denser balls, or alternative materials, shorter milling times may be used. Alterna ⁇ tively, a different milling technique may be used, for example using a re-circulated low fluid energy mill, or other method that results in the removal of grains from the surfaces of the particles, for example sieving, or cyclone treatment.
  • the size of the particles is important and the method may further include the step of selecting an advantageous range of size of particles prior to the treatment step.
  • step (c) mixing the treated particles obtained in step (b) with active particles such that active particles adhere to the surfaces of the carrier particles and/or the additive material.
  • a satisfactory dry powder may also be obtained by mixing the active particles, the additive material and the carrier particles together in one step.
  • the carrier particles may first be mixed with the active particles, followed by mixing with the additive material.
  • Satisfactory dry powders may also be obtained by an alternative sequence of steps.
  • the carrier particles, additive material and active particles may be mixed together followed by a milling step.
  • the carrier particles may first be milled before the addition of additive material and active particles.
  • the invention also provides a method of producing a powder for use in dry powder inhalers, the method including the steps of producing particles as described above and mixing the particles with active particles such that active particles adhere to the surfaces of the carrier particles and/or additive material.
  • Figure 1 shows a section through a carrier particle including additive particles on its surfaces
  • Figure 2 is a perspective view of a dry powder inhaler
  • Figure 3 is a sectional diagram of a twin stage impinger
  • Figures 4a & 4b show the effect of a milling treatment on the carrier particle of Figure 1.
  • Example 1
  • Carrier particles were prepared by the following method. Meggle lactose EP D30 (an ⁇ lactose monohydrate: pure crystalline milk sugar) was used. Lactose EP D30 has a useful particle size range and acceptable flow properties. (a) The lactose was sieved by the following method to give samples having particles with a range of diameter from 90 ⁇ m to 125 ⁇ m. Successive samples of about 500g, of lactose were sieved mechanically for 40 minutes using successively woven wire stainless steel sieves of aperture diameters 63 ⁇ m, 90 ⁇ m and 125 ⁇ m. The mesh was vibrated at high speed on a Boulton rotary gyrator to reduce the binding of lactose particles to the mesh of the sieve.
  • the leucine particles used were of a size such that 95% by weight of the particles had a diameter of less than 150 ⁇ m.
  • the mixture obtained contained approximately 1% leucine by weight.
  • Figure 1 shows a representation of a particle 1 having asperities 2 and clefts 3.
  • the additive particles 4 have become attached to the surface of the particle, mostly at the active sites on the surface. As can be seen from Fig. 1, the additive particles 4 cover only parts of the surface of the particle, other parts of the surface remain ⁇ ing exposed.
  • FIG. 1 shows a view of a dry powder inhaler known as a Rotahaler (trade mark of Glaxo) .
  • the inhaler comprises an outer cylindrical barrel 11 and an inner cylindrical barrel 12 of similar radius such that the inner barrel 12 is just able to fit inside the outer barrel 11.
  • a mesh 13 is attached across an end of the inner barrel 12 and a mouth ⁇ piece 14 is attached around that end section of the inner barrel 12.
  • the outer barrel 11 is closed at one end by an end section 15 which contains inlet slots 16 and an aperture 17.
  • the inner barrel 12 also contains a fin 18 along a length of the inner barrel at the open end, the fin extending radially inwards from the internal surface of the inner barrel 12.
  • the inner barrel 12 is inserted into the open end of the outer barrel 11 such that the mouthpiece meets the outer barrel 11 and the open end of the inner barrel is at the end section 15.
  • Capsule 19 containing the mixture of carrier particles and active particles is inserted into the aperture 17 such that a portion of the capsule 19 is held in the end section 15, and a portion of the capsule 19 extends into the inner barrel 12.
  • the outer barrel 11 is rotated relative to the inner barrel 12 and thus the fin 18 engages and breaks the capsule.
  • a patient inhales through the mouthpiece 14, air is drawn into the Rotahaler through the inlet slots 16, and the contents of the capsule are discharged into the inner barrel as a cloud of powder and inhaled via the mouthpiece 1 .
  • FIG. 3 shows a diagrammatic arrangement of a twin stage impinger (TSI) .
  • the TSI is a two stage separation device used in the assessment of oral inhalation devices. Stage one of the apparatus is shown to the right of the line AB in Figure 3 and is a simulation of the upper respiratory tract. To the left of that line is stage two which is a simulation of the lower respiratory tract.
  • the TSI comprises a mouth 21 which comprises a polydimethylsiloxane adaptor, moulded to accept the mouthpiece of the inhaler device, upper tubing 22 and upper impinger 23 to simulate the upper respiratory tract, the upper impinger containing liquid 24, and lower tubing 25 and lower impinger 26 to simulate the lower respiratory tract, the lower impinger containing liquid 27.
  • the lower impinger 26 is connected via an outlet pipe 28 to a pump 29 which draws air through the TSI apparatus at a predetermined rate.
  • the base of the lower tubing 25 is below the level of the liquid 27 such that all the air drawn through the TSI bubbles through the lower liquid 27.
  • the liquid used in both the upper and lower impinger is a suitable solvent for the drug to be tested.
  • the inhaler is placed in a mouth
  • Air is caused to flow through the apparatus by means of a pump 29 which is connected to stage two of the TSI. Air is sucked through the apparatus from the mouth 21, flows through upper tubing 22 via the upper impinger 23 and the lower tubing 25 to the lower impinger 26 where it bubbles through liquid 27 and exits the apparatus via outlet pipe 28.
  • the liquid 24 in the upper impinger 23 traps any particle with a size such that it is unable to reach stage two of the TSI.
  • Fine par ⁇ ticles which are the particles able to penetrate to the lungs in the respiratory tract, are able to pass into stage two of the TSI where they flow into the lower impinger liquid 27.
  • the Rotahaler was weighed when empty. One of the prepared capsules was inserted into aperture 17 and the inhaler was reweighed. The mouthpiece 14 of the inhaler was connected to the mouth 21 of the TSI, the outer barrel 11 was rotated to break the capsule 19 and the pump was switched on and timed for a period of ten seconds. The pump was then switched off and the Rotahaler was removed from the TSI, reweighed and the amount of powder lost from the inhaler calculated.
  • the other capsules were tested in the same way in a predetermined random order.
  • the contents of the flasks containing the washing from the stages of the TSI were assayed using High Performance Liquid Chromatography (HPLC) analysis for the content of BDP and compared against standard solutions containing 0.5 ⁇ g/ml and l ⁇ g/ l of BDP.
  • HPLC High Performance Liquid Chromatography
  • the percentage of BDP in each stage of TSI was calculated from the standard response for each capsule and the mean for the treated samples and the untreated samples could be calculated.
  • Table 1 below shows the BDP content (in ⁇ g) recovered from each stage of the TSI as an average for the samples of the treated and the untreated material.
  • the respirable fraction (calculated as the percentage of the total amount of drug emitted from the device, that reaches stage two of the TSI) gives an indication of the proportion of active particles which would reach the deep lung in a patient.
  • the numbers in brackets indicate the coefficient of variation for each value.
  • Table 1 no additive 1% leucine particles added added added.
  • Example 1 (b) 4g of leucine (having 95% of weight of particles having a diameter less than 150 ⁇ m) were added to 196g of lactose particles and blended as described in Example 1 (b) .
  • the mixture obtained contained approximately 2% leucine by weight.
  • Table 2 below shows the BDP content (in ⁇ g) recovered from each stage of the TSI as an average for the samples including the additive particles, and the respirable fraction. The figures for the samples from Example 1 to which no additive particles were added are shown for comparison.
  • Samples (B) were milled at 60 rpm for six hours.
  • Samples (C) and (D) were milled at 40 rpm for two hours and four hours respectively.
  • Example 1 The samples were mixed with active particles as described in Example 1 (c) for the particles including the additive particles and analysed as described in steps (d) to (f) for Example 1.
  • Table 3 shows the BDP content (in ⁇ g) recovered from each stage of the TSI as an average for the milled samples (A) to (B) , and the respirable fraction. The figures for the unmilled (1% leucine added) samples from Example 1 are shown for comparison.
  • FIGs 4a and 4b show the effect of the milling step.
  • the shaded areas 5 of the particle 1 represent the sections removed from the surface of the particle as small grains during the milling.
  • small grains 6 have become reattached to the surface of the particle, mostly at active sites.
  • Y contained lactose particles to which 1% leucine had been added before milling
  • Z contained milled lactose particles to which 1% leucine had been added.
  • the milling was performed in a porcelain ball mill with 1200ml of 20mm plastics balls. The mill was revolved at 60 rpm for six hours.
  • Carr's index for a weight (W) of each sample was determined by measuring the volume ( ⁇ oose ) of weight (W) poured into a 250cm 3 measuring cylinder and tapping the cylinder to obtain constant volume of the sample (V ⁇ a p) .
  • the loose density and the tap density are calculated as W/V loose and W/V tap respectively and Carr's index is calculated from the tapped density and the loose density by the formula
  • Carr's index determined for each sample is given in table 4 below.
  • a Carr's index of less than 25 is usually taken to indicate good flow characteristics; a Carr's index greater than 40 indicates poor flow charac ⁇ teristics.
  • step 4 (c) Several samples of the particles prepared in step 4 (b) above were each milled in a porcelain ball mill (Pascall Engineering Company) with 1200ml of 20mm plastics balls. The samples were each milled at 60 rpm for six hours.
  • Table 5 below shows the BDP content (in ⁇ g) recovered from each stage of the TSI as an average for the milled samples and for the unmilled samples, and the respirable fraction.
  • Table 5 lactose with 0.5% sova lecithin and BDP unmilled milled
  • the mixture obtained contained approximately 1% aspartame by weight.
  • step 5 (c) Several samples of the particles prepared in step 5 (b) above were each milled in a porcelain ball mill (Pascall Engineering Company) with 1200ml of 20 mm plastics balls. The samples were each milled at 60 rpm for six hours.
  • step 5 (c) The milled samples obtained in step 5 (c) above and the unmilled samples obtained in step 5 (b) above were each mixed with active particles as described in Example 1 (c) for the particles including the additive and analysed as described in steps (d) to (f) for Example 1.
  • Table 6 below shows the BDP content (in ⁇ g) recovered from each stage of the TSI as an average for the milled samples and for the unmilled samples, and the respirable fraction.
  • the five amino acids were Leucine, Lysine,
  • Table 8 below shows the BDP content (in ⁇ g) recovered from each stage of the TSI as an average for the samples, and the respirable fraction. The results of the control (as in Example 6) are shown for comparison. Table 8
  • Table 10 shows the SBS content (in ⁇ g) recovered from the device and from each stage of the TSI as an average for the samples.
  • the respirable fraction (RF) is also shown and the number in brackets indicates the coefficient of variation of the value.
  • the resulting mixture was blended for four minutes and then dried on trays at 40"C for 6 hours.
  • the powder was screened through a 500 ⁇ m sieve.
  • the powder samples obtained contained approximately 0.5% soya lecithin by weight.
  • Table 11 shows the BDP content (in ⁇ g) recovered from each stage of the TSI as an average for the samples, and the respirable fraction.
  • Stage 1 88.0 (4.7) 71.9 (3.5)
  • Stage 2 1.3 (40.5) 3.4 (11.4)
  • Samples of milled lactose including leucine as additive material were prepared and tested using the TSI to investigate the effect of using different dry powder inhaler devices and different drugs.
  • the milled samples of lactose and leucine were prepared as follows: (a) Samples of lactose having particles within a range of diameter from 90 to 125 ⁇ m were prepared as in Example 1(a) above. (b) Samples of lactose particles obtained in 11(a) were treated by adding leucine particles to the lactose particles and milling the mixture.
  • Table 12 below shows the active material (BDP, SBS, BSN) content (in ⁇ g) for the device and stages 1 and 2 of the TSI and the respirable fraction. The results shown are the average of the replicate tests performed. The figures in brackets show the coefficient of variation. The results shown are in respect of the three different inhaler devices: Rotahaler (RH) , Diskhaler (DH) and Cyclohaler (CH) for both the commercial formulation (C) and the powder containing leucine as additive (L) .
  • RH Rotahaler
  • DH Diskhaler
  • CH Cyclohaler
  • each powder sample is then determined using the same HPLC analysis as employed for the TSI experiments, as described in Example 1 (f) .
  • the quantity of drug (as determined by HPLC) in each sample is expressed as a percentage of the original recorded weight of the powder sample.
  • the values for all the samples are then averaged to produce a mean value, and the coefficient of variation (CV) around this mean calculated.
  • the coefficient of variation is a direct measure of the homogeneity of the mix.
  • the following procedure is then used to simulate the effects of pharmaceutical processing conditions on the homogeneity of the dry powder formulations.
  • the cylinder tower filled with dry powder formulation as described above, is attached to an electronic vibration unit.
  • the instrument is set to a frequency of 50Hz, with a vibrational amplitude of 2g, and is switched on to vibrate the cylinder containing the test powder vertically for 15 minutes.
  • the purpose of the vibration is to subject the powder to treatment comparable to that which it might experience during commercial processing.
  • the homogeneity of the dry powder formulation is then assessed using substantially the procedure described above.
  • the vibrations will cause the powder to compact, with the result that, for example, the three uppermost cylinders may not contain any powder at the end of the vibration. Such cylinders are not included in the statistical analysis.
  • Samples of powder including L-leucine and magnesium stearate as additive materials were prepared and the tendency of the powders to segregate quantitatively assessed.
  • the details of the procedure adopted were as follows: (a) Samples of lactose having particles within a range of diameters from 90-125 ⁇ m were prepared as in Example 1 (a) above.
  • step (d) The powders obtained from step (c) were then subjected to the segregation test described above employing a tower of plastic cylinders. For each powder a first test was carried out without vibration to enable an initial homogeneity, expressed as a percentage coefficient of variation, to be determined; and a second test was carried out after vibration to enable a post-vibration homogeneity, expressed again as a percentage coefficient of variation, to be determined. For the second test, it was found that the top three cylinders were substantially empty after vibration and therefore no results for those cylinders were included in the statistical analysis.
  • the poor initial homogeneity of the 1.5% magnesium stearate mix indicates the very strong tendency of the mix to segregate.
  • the post-vibration results confirm the poor stability of the mix when subjected to conditions comparable to those that might occur during commercial processing.
  • a 1.5% magnesium stearate mix may provide satisfactory results in terms of a respirable fraction, it does not meet the other important requirement of retaining homogeneity during conditions that are comparable to those that might occur during commerical processing.
  • the powders containing leucine, as well as providing a satisfactory respirable fraction had excellent initial homogeneities and the homogeneities remained satisfactory even after intense vibration.

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Abstract

Une poudre à utiliser dans un inhalateur à poudre sèche comprend des particules actives et des particules porteuses servant au transport de ces dernières. Cette poudre porte, de surcroît, sur les faces des particules porteuses, un additif (4) destiné à permettre aux particules actives de se dégager facilement des porteuses lors de la mise en fonctionnement de l'inhalateur. Cette poudre est agencée de telle façon que les particules actives ne sont pas susceptibles de se dégager des porteuses avant la mise en fonctionnement de l'inhalateur. Il s'est avéré que l'adjonction d'additif (4) dans la poudre majorait la partie inhalable de la substance active.
PCT/GB1996/000215 1995-01-31 1996-01-31 Particules porteuses a utiliser dans des inhalateurs a poudre seche WO1996023485A1 (fr)

Priority Applications (27)

Application Number Priority Date Filing Date Title
EE9700176A EE9700176A (et) 1995-01-31 1996-01-31 Kuivpulbriinhalaatorites kasutatav pulber, selle valmistamismeetod, selles kasutatavad osakesed ja meetod nende valmistamiseks ning pulbri lisandi kasutamine
HU9802209A HU229965B1 (hu) 1995-01-31 1996-01-31 Száraz por inhalátorban alkalmazható hordozó részecskék
EA199700153A EA000352B1 (ru) 1995-01-31 1996-01-31 Частицы-носители для использования в ингаляторах для сухого порошка
AT96901439T ATE256450T1 (de) 1995-01-31 1996-01-31 Pulver zur verwendung in trockenpulverinhalatoren
NZ300654A NZ300654A (en) 1995-01-31 1996-01-31 Carrier particles and active particles with additive material for use in dry inhalers
SK1036-97A SK282630B6 (sk) 1995-01-31 1996-01-31 Prášok na použitie v inhalátore na suché prášky, spôsob jeho výroby
BRPI9612950A BRPI9612950B8 (pt) 1995-01-31 1996-01-31 pó para uso em inaladores de pó seco.
DK02007397T DK1232745T3 (da) 1995-01-31 1996-01-31 Pulver til anvendelse i törpulverinhalatorer
BRPI9607490 BR9607490A (pt) 1995-01-31 1996-01-31 Partículas condutoras para uso em inaladores de pó seco
AU45456/96A AU699131B2 (en) 1995-01-31 1996-01-31 Carrier particles for use in dry powder inhalers
GEAP19963854A GEP19991687B (en) 1995-01-31 1996-01-31 Powder for Use in Dry Powder Inhalers and Process for Its Production
DE69631119T DE69631119T2 (de) 1995-01-31 1996-01-31 Pulver zur verwendung in trockenpulverinhalatoren
UA97084422A UA61051C2 (en) 1995-01-31 1996-01-31 Powder for use in dry powder inhaler (variants), method for producing powder (variants), particles used in powder (variants), method for their manufacture and additive material
EP96901439A EP0806938B1 (fr) 1995-01-31 1996-01-31 Poudre a utiliser dans des inhalateurs a poudre seche
CNB961926767A CN1303974C (zh) 1995-01-31 1996-01-31 用于干粉吸入器的载体颗粒
JP52335096A JP4042867B2 (ja) 1995-01-31 1996-01-31 ドライパウダー吸入器に用いられるキャリア粒子
DK96901439T DK0806938T3 (da) 1995-01-31 1996-01-31 Pulver til anvendelse i tørpulverinhalatorer
PL96321572A PL186757B1 (pl) 1995-01-31 1996-01-31 Proszek do stosowania w suchym inhalatorze proszkowym i sposób wytwarzania proszku do stosowania w suchym inhalatorze proszkowym
US08/875,391 US6153224A (en) 1995-01-31 1996-01-31 Carrier particles for use in dry powder inhalers
CA002211874A CA2211874C (fr) 1995-01-31 1996-01-31 Particules porteuses a utiliser dans des inhalateurs a poudre seche
IS4531A IS4531A (is) 1995-01-31 1997-07-25 Endurbætur á og efni tengd útbúnaði fyrir duft-innöndunartæki
NO19973502A NO324037B1 (no) 1995-01-31 1997-07-30 Pulver for anvendelse i en torrpulverinhalator og fremgangsmate for fremstilling av pulveret
FI973151A FI119676B (fi) 1995-01-31 1997-07-30 Kuivajauheinhalaattorissa käytettäväksi tarkoitettu jauhe
BG101858A BG101858A (bg) 1995-01-31 1997-08-27 Прахообразен носител за използване в инхалатори за сух прах
US10/306,865 US7011818B2 (en) 1995-01-31 2002-11-27 Carrier particles for use in dry powder inhalers
US11/202,741 US7718163B2 (en) 1995-01-31 2005-08-11 Carrier particles for use in dry powder inhalers
US12/748,275 US8920781B2 (en) 1995-01-31 2010-03-26 Carrier particles for use in dry powder inhalers

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9501841.2A GB9501841D0 (en) 1995-01-31 1995-01-31 Improvements in and relating to carrier particles for use in dry powder inhalers
GB9501841.2 1995-01-31
GBGB9521937.4A GB9521937D0 (en) 1995-01-31 1995-10-26 Improvementsin and relating to carrier particles for use in dry powder inhailers
GB9521937.4 1995-10-26

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US08/875,391 A-371-Of-International US6153224A (en) 1995-01-31 1996-01-31 Carrier particles for use in dry powder inhalers
US08875391 A-371-Of-International 1996-01-31
US09/680,863 Continuation US6521260B1 (en) 1995-01-31 2000-10-06 Carrier particles for use in dry powder inhalers

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WO1996023485A1 true WO1996023485A1 (fr) 1996-08-08

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EP (6) EP0806938B1 (fr)
JP (1) JP4042867B2 (fr)
KR (1) KR100500694B1 (fr)
CN (1) CN1303974C (fr)
AT (3) ATE355822T1 (fr)
AU (1) AU699131B2 (fr)
BG (1) BG101858A (fr)
BR (3) BR9612950B1 (fr)
CA (1) CA2211874C (fr)
CZ (1) CZ294259B6 (fr)
DE (2) DE69636961T2 (fr)
DK (3) DK1666023T3 (fr)
EA (1) EA000352B1 (fr)
EE (1) EE9700176A (fr)
ES (3) ES2213172T3 (fr)
FI (1) FI119676B (fr)
GB (2) GB9501841D0 (fr)
GE (1) GEP19991687B (fr)
HK (1) HK1084897A1 (fr)
HU (1) HU229965B1 (fr)
IS (1) IS4531A (fr)
MX (1) MX9705847A (fr)
NO (1) NO324037B1 (fr)
NZ (1) NZ300654A (fr)
PL (1) PL186757B1 (fr)
PT (3) PT1232745E (fr)
SI (2) SI1232745T1 (fr)
SK (1) SK282630B6 (fr)
TR (1) TR199700722T1 (fr)
UA (1) UA61051C2 (fr)
WO (1) WO1996023485A1 (fr)
ZA (1) ZA96721B (fr)

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KR100500694B1 (ko) 2006-03-22
ES2375007T3 (es) 2012-02-24
US7718163B2 (en) 2010-05-18
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PT1232745E (pt) 2007-04-30
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ZA96721B (en) 1996-08-19
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ES2213172T3 (es) 2004-08-16
AU4545696A (en) 1996-08-21
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UA61051C2 (en) 2003-11-17
EP2258342A2 (fr) 2010-12-08
PL186757B1 (pl) 2004-02-27
KR19980701844A (ko) 1998-06-25
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US20060029552A1 (en) 2006-02-09
EA199700153A1 (ru) 1997-12-30
SI1232745T1 (sl) 2007-06-30
EP0806938B1 (fr) 2003-12-17
HU229965B1 (hu) 2015-03-30
DK1666023T3 (da) 2012-01-30
JPH10513174A (ja) 1998-12-15
EA000352B1 (ru) 1999-04-29
CN1303974C (zh) 2007-03-14
US20100330188A1 (en) 2010-12-30
HUP9802209A3 (en) 2000-06-28
SI1666023T1 (sl) 2012-01-31
CZ294259B6 (cs) 2004-11-10
AU699131B2 (en) 1998-11-26
HUP9802209A2 (hu) 1999-02-01
US7011818B2 (en) 2006-03-14
US8920781B2 (en) 2014-12-30
HK1084897A1 (en) 2006-08-11
US6153224A (en) 2000-11-28
FI119676B (fi) 2009-02-13
ATE526946T1 (de) 2011-10-15
BG101858A (bg) 1998-04-30
EP1666023A2 (fr) 2006-06-07
DK0806938T3 (da) 2004-04-13
FI973151L (fi) 1997-09-30
EP1232745A1 (fr) 2002-08-21
EP2213279A2 (fr) 2010-08-04
EP1666023A3 (fr) 2009-05-06
EP2258342A3 (fr) 2014-01-08
PT1666023E (pt) 2012-01-12
BR9612950B1 (pt) 2011-08-23
BR9607490B8 (pt) 2018-04-17
US6521260B1 (en) 2003-02-18
SK103697A3 (en) 1998-01-14
EP1666023B1 (fr) 2011-10-05
ES2278828T3 (es) 2007-08-16
BRPI9612950B1 (fr) 2011-08-23
EP2213279A3 (fr) 2010-10-13
ATE355822T1 (de) 2007-03-15
NO973502L (no) 1997-09-30
CN1179097A (zh) 1998-04-15
DE69636961D1 (de) 2007-04-19
US20030170183A1 (en) 2003-09-11
IS4531A (is) 1997-07-25
CZ244397A3 (cs) 1998-01-14
DE69636961T2 (de) 2007-06-14
PL321572A1 (en) 1997-12-08
EP0806938A1 (fr) 1997-11-19
BR9607490A (pt) 2018-04-17
CA2211874C (fr) 2006-08-29
DK1232745T3 (da) 2007-07-09
GB9521937D0 (en) 1996-01-03
ATE256450T1 (de) 2004-01-15
JP4042867B2 (ja) 2008-02-06
NO973502D0 (no) 1997-07-30
DE69631119T2 (de) 2004-09-16
TR199700722T1 (xx) 1998-02-21
EP1232745B1 (fr) 2007-03-07
FI973151A0 (fi) 1997-07-30
EE9700176A (et) 1998-02-16
SK282630B6 (sk) 2002-10-08
PT806938E (pt) 2004-05-31

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